Method for preventing the crystallisation of pharmaceuticals in a polymer film

ABSTRACT

The invention relates to a method for preventing the crystallization of a pharmaceutical in a polymer film, wherein the solvent-containing coating compound, which comprises a matrix-forming polymer or polymer mixture and at least one pharmaceutical and is spread to produce the polymer film, is temporarily dried at temperatures that is at least 10° C. above the melting temperature of the pharmaceutical contained in the coating compound. The maximum temperature is thus higher than that which is required for mere drying and obviates the need for an additional, time-consuming and expensive work step.

The present invention relates to a method for preventing the spontaneouscrystallization of a pharmaceutical in a polymer film. A “spontaneouscrystallization” here means a crystallization which takes place withoutany perceptible stimulus.

Transdermal therapeutic systems are administration forms forpercutaneous administration of pharmaceuticals. Among transdermaltherapeutic systems, a distinction is made between reservoir systems andmatrix systems. In the case of the reservoir systems, the pharmaceuticalis present in the form of a liquid or semiliquid preparation in a flatreservoir whose wall comprises a membrane via which the pharmaceuticalpresent in the reservoir can be delivered. Matrix systems aredistinguished by the fact that the pharmaceutical is present in apolymer film. In their simplest embodiment, matrix systems consist of apharmaceutical-impermeable backing layer, a pharmaceutical-containingmatrix layer, which is usually self-adhesive, and a protective layerwhich is to be removed before use. However, there are also matrixsystems of more complex construction, which may have two or more matrixlayers of different compositions, an additional control membrane and/orelse non-self-adhesive layers.

Pharmaceutical-containing polymer films are also in use, furthermore,for drugs intended for oral administration, as for example in the formof administration forms in sheet or film form. These drugs for oraladministration may be based on a water-soluble polymer, and so thepharmaceutical is released rapidly when the administration form comesinto contact with saliva. Water-insoluble or sparingly water-solublepolymers, preferably having mucoadhesive properties, are used foradministration forms in sheet or film form with delayed release and/orfor transmucosal administration of the pharmaceutical in the oralcavity.

Pharmaceutical-containing polymer films for oral or transdermaltherapeutic systems are generally produced by applying a coatingmaterial, comprising the matrix-forming polymer or polymer mixture andthe pharmaceutical, in a defined thickness to a substrate and thendrying it. The coating of the substrate and the drying of the coatingtake place typically in one continuous operation. Drying in this contextgenerally means the removal of the solvents.

The coating material is a solution or suspension comprising thematrix-forming polymer or the matrix-forming polymer mixture, at leastone pharmaceutical, and optionally further excipients, examples beingpermeation enhancers, plasticizers, flavors, colorants, preservatives,antioxidants or the like in a solvent. The solvent is preferably anorganic solvent or a mixture of organic solvents.

The pharmaceutical itself may be, but need not be, completely dissolvedin the solvent. In those cases where the pharmaceutical is to be fullydissolved in the solvent, there is a risk, even on slight exceedance ofthe saturation solubility for the pharmaceutical in the coatingmaterial, that crystallization nuclei will form in the coating materialduring coating of the substrate. Within the body of the coating, suchcrystallization nuclei are able to form as a result of a locally greaterevaporation of the solvent or of one solvent component of the solventmixture, and of a resultant local crystallization of the pharmaceutical.

The local crystallization of the pharmaceutical in the coating materialis not a problem if the dried, solvent-free polymer film is subsaturatedwith pharmaceutical, since under these conditions the crystallizationnuclei break up within a short time. The local crystallization of thepharmaceutical in the coating does constitute a problem, however, if thedried polymer film is also supersaturated with pharmaceutical orcomprises pharmaceutical in an amorphous modification. Matrix systemssupersaturated with pharmaceutical—and this includes systems whichcomprise the pharmaceutical in an amorphous form—have the advantage ofparticularly high thermodynamic activity and bioavailability of thepharmaceutical. This advantage, however, is contrasted by thedisadvantage that the supersaturated matrix systems are metastable andthe bioavailability of the pharmaceutical is severely adversely affectedby its crystallization.

In order to prevent the formation of crystalline hydrates of activeingredients liquid at room temperature in a polymeric matrix layer, U.S.Pat. No. 4,832,953 proposed heating the pharmaceutical-containingpolymer matrix. Described specifically is the formation of scopolaminehydrate crystals in nonaqueous, polymeric matrices, and an associated,significantly disadvantageous effect on the rate of release ofscopolamine from the administration units, in which liquid scopolaminebase is present in dispersion in a polyisobutylene/mineral oil matrix.To solve this problem, it is proposed that the ready-packedadministration units be heated to 60° C. for a period of 24 hours. Thisheating of the administration units was sufficient to melt crystals ofthe scopolamine base hydrate present in the matrix, with a melting pointof 59° C., and to prevent formation of crystals after the cooling of theadministration units.

With administration units treated in this way, however, the occurrenceof additional crystals was observed which had a relatively high meltingtemperature of 67-70° C. These additional crystals were not eliminatedby the heating of the administration units to 60° C. for 24 hours. Norwas it possible to eliminate these additional crystals by raising thetemperature to which the packaged administration units were heated. Inorder to solve this problem, U.S. Pat. No. 5,662,928 proposes heatingthe scopolamine-containing matrix layer—in addition to the heattreatment of the completed and ready-packaged administration units—to atemperature of between 67° C. and 90° C. for a period of 5 to 15minutes, immediately prior to lamination with the release-controllingmembrane. “Immediately”, according to U.S. Pat. No. 5,662,928, meansthat the lamination must take place within 24 hours, better still within18 hours, after application of the scopolamine coating.

This known method for preventing crystallization of the pharmaceuticalin the polymer matrix has the disadvantage that the matrix layer, afterit has been coated, must be further-processed within a short time (24hours) and can no longer be stored in the interim. This further heattreatment is an additional production step and renders the productionmethod time-consuming and hence also costly.

The object on which the present invention was based was to find a simpleand cost-effective way to prevent the crystallization of pharmaceuticalin a polymer matrix supersaturated with this pharmaceutical.

The object is achieved in a surprisingly simple way by subjecting thecoating, which comprises at least the polymer or polymer mixture and thepharmaceutical, to drying, to remove the solvent, at temperatures whichat times are at least 10° C. above the melting temperature of thepharmaceutical.

The present invention therefore relates to a method for preventing thecrystallization of a pharmaceutical in a pharmaceutical-containingpolymer film which is suitable for producing transdermal therapeuticsystems or drugs intended for oral administration. A feature of themethod is that a substrate is coated with a coating material comprisinga solvent or solvent mixture, a matrix-forming polymer or polymermixture and at least one pharmaceutical, and the solvent or solventmixture is removed from the coating with application of heat, themaximum temperature during removal of the solvent at times exceeding themelting temperature of the pharmaceutical by at least 10° C. and thusbeing higher than is necessary for pure drying.

In one preferred embodiment the maximum temperature during the drying ofthe pharmaceutical-containing coating is at times 10° C. to 25° C. abovethe melting temperature of the pharmaceutical.

Drying temperatures above 130° C., however, may be problematic, sinceeven heat-resistant polyester films, which are frequently used as asubstrate for the coating, begin to soften at these temperatures.

The drying of the pharmaceutical-containing coating ought to take placefor at least 1 minute, preferably for at least 1.5 minutes, and morepreferably for at least 3 minutes at a temperature which is more than10° C. above the melting temperature of the pharmaceutical.

The drying of the pharmaceutical-containing coating ought to take placefor not longer than 15 minutes, preferably not longer than 10 minutes,and more preferably not longer than 5 minutes at a temperature which ismore than 10° C. above the melting temperature of the pharmaceutical.

The pharmaceutical-containing polymer films are typically produced byadding at least one pharmaceutical and optionally further excipients toa solution or suspension of the matrix-forming polymer or polymermixture. The coating material thus obtained is coated on a sheetlikesubstrate to form a coating having a defined thickness. The coatedsubstrate is then passed through a drying tunnel, in which the solventor solvent mixture is removed at elevated temperature, leaving onlysmall residual amounts of solvent, not more than 0.5% by weight, in thecoating.

In one preferred embodiment the pharmaceutical is dispersed in the formof a solid solution in the matrix-forming polymer. A “solid solution” isa molecularly disperse distribution of the pharmaceutical in the matrixpolymer.

An objective when specifying the drying conditions is to remove thesolvent/solvents under extremely gentle conditions. The solvent isselected by the skilled person in dependence on the matrix polymer. Thecommon solvents are heptane, hexane, cyclohexane, ethyl acetate,ethanol, methanol, isopropanol, and tetrahydrofuran.

The matrix-forming polymer itself is not a limiting factor for themethod of the invention. Examples of suitable matrix-forming polymersinclude polysiloxanes, polyacrylates, polyisobutylenes, block copolymerssuch as styrene-butadiene-styrene block copolymers, and mixturesthereof. Particularly preferred matrix-forming polymers areamine-resistant polysiloxanes.

The matrix-forming polymers are preferably pressure-sensitive adhesiveor self-adhesive polymers.

Suitable pharmaceuticals for the method of the invention are the activepharmaceutical ingredients which have a melting point of less than 120°C. It is preferred to use active pharmaceutical ingredients whosemelting point is below 115° C. Particularly preferred for use are activepharmaceutical ingredients whose melting point is below 105° C.Especially preferred pharmaceuticals are rotigotine and fentanyl.

EXAMPLE 1 (COMPARATIVE EXAMPLE)

A two-phase system was produced, with an outer phase composed of aself-adhesive polysiloxane polymer and an inner phase composed of apolyvinylpyrrolidone/pharmaceutical complex. The coating materialconsisted of a dispersion in which the polysiloxane adhesive of theouter phase was present in solution in n-heptane, and thepharmaceutical, rotigotine, and the polyvinylpyrrolidone of the innerphase were present in solution in ethanol. The pharmaceutical,rotigotine, has a melting temperature of 97-99° C. and the saturationsolubility in the coating material is exceeded at room temperature.

The coating was dried in a drying tunnel having the temperature profileindicated in table 1.

TABLE 1 Temperature profile for the drying of a polymer film comprisingrotigotine. Temperature [° C.] 40 50 55 60 70 80 Time [s] 50 50 50 50 7070The coating operation produced numerous crystallization nuclei withinthe polymer film, which were not visible immediately after coating. Just24 hours after its drying, the polymer film exhibited microscopicallyvisible crystallization of the pharmaceutical within the matrix. After 2days, the crystallization of the pharmaceutical throughout the laminatewas evident even to the naked eye.

EXAMPLE 2

A rotigotine-containing coating material was produced as described inexample 1 and was coated in the same way onto a substrate. As adeparture from example 1, this coating was dried with the temperatureprofile indicated in table 2.

TABLE 2 Temperature profile for the drying of a polymer film comprisingrotigotine in accordance with the method of the invention. Temperature[° C.] 40 50 60 70 80 90 100 105 115 Time [s] 50 25 25 25 25 25 25 50100With this drying method, the coating at the end of drying was exposedfor a period of just under 3 minutes to a temperature which was abovethe melting temperature of the pharmaceutical of 97-99° C.

For the pharmaceutical-containing polymer film dried in accordance withthe temperature profile indicated in table 2, no crystallization of thepharmaceutical in the polymer matrix could be found even 2 years aftercoating.

The higher drying temperature with the method according to example 2 hascompletely prevented the crystallization of rotigotine in the polymermatrix as a consequence of the formation of seed crystals duringcoating.

1. A method for preventing the crystallization of a pharmaceutical in apolymer film, comprising applying a solvent-containing coating materialto produce a polymer film, said coating material further comprising amatrix-forming polymer or polymer mixture and at least onepharmaceutical present in dissolved form and having a meltingtemperature, drying the coating material at temperatures which are attimes 10 to 25° C. above the melting temperature of the pharmaceuticalpresent in the coating material.
 2. The method of claim 1, wherein thetemperatures are at times 15 to 25° C. above the melting temperature ofthe pharmaceutical.
 3. The method of claim 1, wherein the dryingtemperature does not exceed 130° C.
 4. The method of claim 1, whereinthe coated material is dried for at least 1 minute at the temperaturewhich is at least 10° C. above the melting point of the pharmaceutical.5. The method of claim 1, wherein the coated material is dried for notlonger than 15 minutes at the temperature which is at least 10° C. abovethe melting point of the pharmaceutical.
 6. The method of claim 1,wherein the matrix-forming polymer or at least one of the polymers ofthe matrix-forming polymer mixture is selected from the group consistingof polysiloxanes, polyacrylates, polyisobutylenes, and block copolymers.7. The method of claim 1, wherein the matrix-forming polymer is anamine-resistant polysiloxane.
 8. The method of claim 1, wherein thesolvent is selected from the group of organic solvents consisting ofheptane, hexane, cyclohexane, ethyl acetate, ethanol, methanol,isopropanol, and tetrahydrofuran.
 9. The method of claim 1, wherein thepharmaceutical has a melting temperature of below 120° C.
 10. The methodof claim 1, wherein the pharmaceutical is selected from the groupcomprising rotigotine and fentanyl.
 11. The method as claimed in claim4, wherein the coated material is dried for at least 100 seconds. 12.The method as claimed in claim 4, wherein the coated material is driedfor at least 3 minutes.
 13. The method as claimed in claim 5, whereinthe coated material is dried for not longer than 10 minutes.
 14. Themethod as claimed in claim 5, wherein the coated material is dried fornot longer than 5 minutes.
 15. The method as claimed in claim 9, whereinthe pharmaceutical has a melting temperature of below 115° C.
 16. Themethod as claimed in claim 9, wherein the pharmaceutical has a meltingtemperature of below 105° C.